Crystalline forms of thiazolidinedione compound and its manufacturing method

ABSTRACT

A crystalline form of a hydrate of a dihydrochloride 5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dione represented by the following formula: 
                         
wherein the crystalline form shows main peaks at interplanar spacings of 10.42, 5.85, 5.52, 3.84, 3.46 and 2.95 angstroms in X-ray powder diffraction obtained with Cu Kα line radiation (wavelength λ=1.54 angstroms).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.12/311,610 filed Apr. 6, 2009 (U.S. Pat. No. 8,236,834), which is theUnited States national phase application under 35 USC 371 ofInternational application PCT/JP2008/052594 filed Feb. 8, 2008. U.S.Ser. No. 12/311,610 and PCT/JP2008/052594 are incorporated by referenceherein in their entirety. Priority is claimed under 35 USC 119(e) ofU.S. provisional application Ser. No. 60/900,251 filed Feb. 8, 2007.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to crystalline forms of athiazolidinedione compound having a significant ability of peroxisomeproliferator-activated receptor (PPAR) γ activation, a significantanticancer activity and favorable properties for manufacturingmedicaments, as well as being highly pure and excellent in preservationstability and handleability, manufacturing methods thereof, andmedicines containing as an active component the crystalline forms of thethiazolidinedione compound (in particular, PPARγ activators oranticancer pharmaceutical compositions).

2. Description of the Related Art

Japanese Patent No. 3488099 (International Patent Application Laid-OpenNo. 99/18081, U.S. Pat. No. 6,432,993, European Patent No. 1022272)(Patent Literature 1), Japanese Patent Laid-Open No. 2003-238406(International Patent Application Laid-Open No. WO03/053440) (PatentLiterature 2), Japanese Patent Laid-Open No. 2004-083574 (WO2004/000356)(Patent Literature 3), Japanese Patent Laid-Open No. 2005-162727(WO2004/083167) (Patent Literature 4), and International PatentApplication Laid-Open No. 2007/091622 (Patent Literature 5) disclose athiazolidinedione compound represented by the after-mentioned formula(I) (abbreviated as Compound (I) hereinafter.). Compound (I) has asignificant ability of peroxisome proliferator-activated receptor (PPAR)γ activation and is expected to exert its availability as a PPARγactivator or an anticancer pharmaceutical composition.

In general, substances used in pharmaceutical products are required tohave high purity to avoid unexpected adverse effects caused byimpurities of the substances. The impurities include by-products (analogsubstances) being produced during the manufacture of the pharmaceuticalingredients themselves, raw materials and solvents being used formanufacturing the pharmaceutical ingredients and the like. Also, thesubstances are required to have more favorable physical and chemicalproperties for manufacturing medicaments such as crystal forms ofpharmaceutical ingredients which are resistant to a heat treatment stepand the like for preparation, or high solubility which makespharmaceutical ingredients able to increase their absorbability so thatthey can exert their effects at lower doses. Moreover, it is importantthat the pharmaceutical ingredients can be stored for long periods oftime, while maintaining the quality. In addition, large-scalerefrigerating installations are needed to maintain the quality ofpharmaceutical ingredients if they are required to be stored at lowtemperatures. Therefore, it is industrially significant to findcrystalline forms which are stable and such as can be stored at roomtemperature or even higher temperatures.

As mentioned above, an industrial and large-scale manufacturing methodis required to manufacture pharmaceutical ingredients being more highlypure, having favorable properties for manufacturing medicaments andbeing stockable while stably maintaining their purity and properties forlong periods of time.

-   [Patent Literature 1] Japanese Patent No. 3488099 (Pamphlet of    International Patent Application Laid-Open No. 99/18081,    Specification of U.S. Pat. No. 6,432,993, Specification of European    Patent No. 1022272)-   [Patent Literature 2] Japanese Patent Laid-Open No. 2003-238406    (Pamphlet of international Patent Application Laid-Open No.    WO03/053440)-   [Patent Literature 3] Japanese Patent Laid-Open No. 2004-083574    (Pamphlet No. WO2004/000356)-   [Patent Literature 4] Japanese Patent Laid-Open No. 2005-162727    (Pamphlet No. WO2004/083167)-   [Patent Literature 5] Pamphlet of International Patent Application    Laid-Open No. 2007/091622

The present inventors have done earnest research on Compound (I) whichhas a significant ability of peroxisome proliferator-activated receptor(PPAR) γ activation and is expected to exert its availability as a PPARγ activator or an anticancer pharmaceutical composition. As a result,the inventors found novel crystalline forms of hydrates of thedihydrochloride of Compound (I) having significant physical and chemicalproperties as pharmaceutical ingredients, being excellent inpreservation stability at room temperature as well as being highly pure,and manufacturing methods thereof. Based on this finding, the inventorshave achieved the present invention.

SUMMARY OF THE INVENTION

The present invention relates to the followings:

(1) A crystalline form of a hydrate of a dihydrochloride of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionerepresented by the following formula (I);

(2) The crystalline form of a hydrate of a dihydrochloride of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionerepresented by the general formula (I) according to (1) above, whereinthe crystalline form shows main peaks at interplanar spacings of 7.06,5.79, 5.43, 4.44, 4.18, 3.97, 3.91, 3.68, 3.61, 3.48, 3.24 and 2.97angstroms in X-ray powder diffraction obtained with Cu Kα line radiation(wavelength λ=1.54 angstroms) (Crystalline form A);(3) The crystalline form of a hydrate of a dihydrochloride of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionerepresented by the general formula (I) according to (1) above, whereinthe crystalline form shows main peaks at interplanar spacings of 10.42,5.85, 5.52, 3.84, 3.46 and 2.95 angstroms in X-ray powder diffractionobtained with Cu Kα line radiation (wavelength λ=1.54 angstroms)(Crystalline form B);(4) The crystalline form according to (2) above, wherein the impuritycontent ratio measured by HPLC is 2.00% or less;(5) The crystalline form according to (2) above, wherein the impuritycontent ratio measured by HPLC is 1.50% or less;(6) A pharmaceutical composition containing as an active component thecrystalline form of a hydrate of the dihydrochloride of thethiazolidinedione compound represented by the general formula (I)according to any one of (1) to (5) above;(7) A PPARγ activator containing as an active component the crystallineform of a hydrate of the dihydrochloride of the thiazolidinedionecompound represented by the general formula (I) according to any one of(1) to (5) above;(8) An anticancer pharmaceutical composition containing as an activecomponent the crystalline form of a hydrate of the dihydrochloride ofthe thiazolidinedione compound represented by the general formula (I)according to any one of (1) to (5) above;(9) A pharmaceutical composition for preventing or treating diabetes,containing as an active component the crystalline faith of a hydrate ofthe dihydrochloride of the thiazolidinedione compound represented by thegeneral formula (I) according to any one of (1) to (5) above.(10) A pharmaceutical composition for preventing or treating cancer whenoccurring in conjunction with diabetes, containing as an activecomponent the crystalline form of a hydrate of the dihydrochloride ofthe thiazolidinedione compound represented by the general formula (I)according to any one of (1) to (5) above.(11) A method of manufacturing the crystalline form according to (2)above, characterized in that5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneis formed into an aqueous solution thereof, and subsequentlyhydrochloric acid is dripped thereto;(12) A method of manufacturing the crystalline form according to (2)above, characterized in that5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneis formed into an aqueous solution thereof, and subsequentlyhydrochloric acid is dripped thereto to give a crystalline form of ahydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride, which is further dissolved or slurried in water andthen hydrochloric acid is dripped thereto; and(13) A method of manufacturing the crystalline form according to (2)above, characterized in that5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneis formed into an aqueous solution thereof,and subsequently hydrochloric acid is dripped thereto to give acrystalline form of a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride,which is further dissolved or slurried in water,and subsequently base is added thereto to give a solution or slurry,and then hydrochloric acid is dripped thereto.(14) A method of manufacturing the crystalline form according to (2)above, characterized in that5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneis formed into an aqueous solution thereof,and subsequently seeds of a crystalline form of a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride are added while hydrochloric acid is dripped thereto.(15) A method of manufacturing the crystalline form according to (2)above, characterized in that5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneis formed into an aqueous solution thereof,and subsequently hydrochloric acid is dripped thereto to give acrystalline form of a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride,which is further dissolved or slurried in waterand subsequently seeds of a crystalline form of a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride are addedwhile hydrochloric acid is dripped thereto.(16) A method of manufacturing the crystalline form according to (2)above, characterized in that5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneis formed into an aqueous solution thereof,and subsequently hydrochloric acid is dripped thereto to give acrystalline form of a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride,which is further dissolved or slurried in water,and subsequently base is added thereto to give solution or slurry,and then seeds of a crystalline form of a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride are addedwhile hydrochloric acid is dripped thereto.(17) A method of manufacturing the crystalline form according to (3)above, characterized in that a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride is crystallized from methanol.

The crystalline form of a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride represented by (I) above in the present invention(hereinafter may be abbreviated as the crystalline form in the presentinvention) is a solid whose internal structure is composed ofconstituent atoms (or the groups thereof) assembled into regularlystructured 3-dimensional repeats. The crystalline form is distinguishedfrom an amorphous solid, which has no such regularly structured internalstructure.

Even a single compound can be formed into a number of differentcrystalline forms having different internal structures and physical andchemical properties (crystal polymorphs), depending on crystallizationconditions. The crystalline form in the present invention may be any oneof the crystal polymorphs or a mixture of two or more of the crystalpolymorphs.

The crystalline form in the present invention may absorb water and havewater adhere by leaving the same in the atmosphere. The crystalline formin the present invention may also absorb an organic solvent to form asolvate when mixed with the solvent. Moreover, the crystalline form inthe present invention may form a hemihydrate and even an anhydrous formthereof by, for example, heating the same to between 25° C. and 150° C.under normal atmospheric conditions.

The crystalline form in the present invention includes the crystallineform with adhered water, a crystalline form composed of a hydrate orsolvate thereof, a crystalline form containing a hemihydrate thereof anda crystalline form containing an anhydrous form thereof. Among thesecrystalline forms, as the crystalline form in the present invention, acrystalline form of a dihydrochloride monohydrate of Compound (I) ispreferred.

As a form of the crystalline form in the present invention, can beincluded Crystalline form A, which shows main peaks at interplanarspacings of 7.06, 5.79, 5.43, 4.44, 4.18, 3.97, 3.91, 3.68, 3.61, 3.48,3.24 and 2.97 angstroms in X-ray powder diffraction obtained with Cu Kαline radiation (wavelength λ=1.54 angstroms), wherein the main peaks arepeaks which have relative intensities greater than 30% based on theintensity 100 of a peak at an interplanar spacing d=7.06 angstroms andpeaks which are not observed in after-mentioned Crystalline form in thepresent invention.

The interplanar spacing d is calculated according to the equation: 2 dsin θ=nλ, wherein n equals 1.

Another form of the crystalline form in the present invention isCrystalline form B, which shows main peaks at interplanar spacings of10.42, 5.85, 5.52, 3.84, 346 and 2.95 angstroms in X-ray powderdiffraction obtained with Cu Kα line radiation (wavelength λ=154angstroms), wherein the main peaks are peaks which have relativeintensities greater than 20% based on the intensity 100 of a peak at aninterplanar spacing d=3.46 angstroms.

Furthermore, the above mentioned relative intensities of the main peaksmay vary in accordance with differences in crystalline form growthfronts (crystal habits). Such crystalline forms are recognized asidentical in terms of crystalline form and therefore included in thepresent invention.

In the present invention, the level of impurity contained in acrystalline form can be determined by conventional methods in analyticchemistry such as high-performance liquid chromatography (hereinaftermay be abbreviated as HPLC), % by weight, and preferably the peak arearatio by using HPLC. Measurement conditions for HPLC may be arbitrarilyselected. Preferred measurement conditions are described below.

HPLC Measurement Conditions (1)

Detector: UV absorptiometer (wavelength: 230 nm)

Column: Waters Corporation, XTerra RP₁₈ (4.6 mm×150 mm)

Column temperature: 40° C.

Mobile phase: 0.01 mol/ml ammonium acetate buffer-acetonitrile (65:35)

Flow rate: 1 ml/min (Under the present conditions, Compound (I) showed aretention time of approximately 25 minutes.)

Injection amount: 10 μl

Peak area measurement range: 70 minutes after the start of the injection

HPLC Measurement Conditions (2)

Detector: UV absorptiometer (wavelength: 230 nm)

Column: Waters Corporation, XTerra RP₁₈ (4.6 mm×150 mm)

Column temperature: 40° C.

Mobile phase: 0.01 mol/ml ammonium acetate buffer-acetonitrile (56:44)

Flow rate: 1 ml/min (Under the present conditions, Compound (I) showed aretention time of approximately 8 minutes.)

Injection amount: 10 μl

Peak area measurement range: 70 minutes after the peak which elutes nextto the peak whose retention time relative to Compound (I) is 1.48.

Under HPLC Measurement Conditions (I), the peak area ratios are measuredfor Compound (1) and compounds which are impurities detected from 0minute to 70 minutes. Under HPLC Measurement Conditions (2), the peakarea ratios are measured for compounds which are impurities detected for70 minutes after the peak which elutes next to the peak whose retentiontime relative to Compound (I) is 1.48.

The term peak for compounds which are impurities here represents allpeaks whose peak area ratios are measured as 0.01% or more, excludingthe peak for Compound (I) and the peak which is detected when injectingsolvent alone.

In the present invention, the term impurity content ratio measured byHPLC represents the ratio of the integration area for all peaks whosepeak area ratios are measured as 0.01% or more, excluding the peak forCompound (I) and the peak which is detected when injecting solventalone, to the peak area for Compound (I) under the above mentionedconditions by using HPLC.

Among the crystalline forms in the present invention, with regard toCrystalline form A, the impurity content ratio measured by HPLC ispreferably 2.00% or less, and more preferably 1.50% or less.

The crystalline forms in the present invention are highly pure, white intheir color tone, and excellent in preservation stability, handleabilityand the like. Especially, Crystalline form A in the present inventionhas a low amount of residual solvent and is highly pure and white in itscolor tone, and excellent in preservation stability in the form ofhydrate at room temperature because the dehydration temperature of thehydrate is high. Crystalline form B in the present invention has highersolubility than the Compound (I) which has been known. Taken together,the crystalline forms in the present invention are useful as materialsfor manufacturing medicines which are mass-produced in industrialproduction (in particular, PPARγ activators, agents for preventingand/or treating cancers, agents for preventing and/or treating diabetes,or agents for preventing and/or treating cancers when occurring inconjunction with diabetes).

Furthermore, the method of manufacturing the crystalline form in thepresent invention is a useful method for manufacturing materials formedicines which are mass-produced in industrial production, because themethod can reduce the amount of residual solvent, manufacture a highlypure crystalline form, and produce a white crystalline form bydecolorizing the crystalline form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction pattern for Crystalline form Aobtained in Example 1, the vertical axis showing diffraction intensityin units of counts/see (cps), and the horizontal axis showing values ofdiffraction angle 2θ;

FIG. 2 is a differential thermal analysis (DSC) chart for Crystallineform A obtained in Example 1 when the temperature was raised at a rateof 5° C. per minute, the vertical axis showing a heating value persecond (mcal/s) (or endothermic value when the value is negative), andthe horizontal axis showing temperature (° C.);

FIG. 3 is an X-ray powder diffraction pattern for Crystalline form Bobtained in Example 3, the vertical axis showing diffraction intensityin units of counts/sec (cps), and the horizontal axis showing values ofdiffraction angle 2θ;

FIG. 4 is a differential thermal analysis (DSC) chart for Crystallineform B obtained in Example 3 when the temperature was raised at a rateof 5° C. per minute, the vertical axis showing a heating value persecond (mcal/s) (or an endothermic value when the value is negative) andthe horizontal axis showing temperature (° C.); and

FIG. 5 is the X-ray powder diffraction pattern for the compound obtainedin Comparative Example 1. In the figure, the vertical axis showsdiffraction intensity in units of counts/sec (cps), and the horizontalaxis shows values of diffraction angle 2θ.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The above mentioned Compound (I) can be manufactured by the methoddisclosed in Japanese Patent No. 3488099 or a method similar to thatmethod.

The crystalline form in the present invention can be manufactured bydissolving Compound (I) or various salts of Compound (I) or varioussolvates thereof, the dihydrochloride of Compound (I) or varioussolvates thereof, or the hydrate of the dihydrochloride of Compound (I)itself in an adequate solvent, followed by desalination(neutralization), addition of hydrogen chloride or hydrochloric acid,concentration of the solution, cooling, mixing with a good solvent and apoor solvent and the like, which lead to supersaturation conditions toallow precipitation of the hydrate of the dihydrochloride of Compound(I), followed by isolation of the precipitated crystalline form.Moreover, a solution of synthetic crude products containing Compound (I)described above can be used as the solution in which Compound (I) orvarious salts of Compound (I) or various solvates thereof, thedihydrochloride of Compound (I) or various solvates thereof, or thehydrate of the dihydrochloride of Compound (I) itself is dissolved.

The precipitation of the crystalline form can be spontaneously initiatedin a reaction container, but also can be initiated or promoted by givingmechanical stimulus thereto, such as seed crystalline form inoculation,ultrasonic stimulation and rubbing the surface of the reactor.

The obtained crystalline form can be subjected to recrystallization andslurry purification to further improve the purity and quality thereof.

In cases where various salts of Compound (I) or various solvates thereofare used, desalination (neutralization) may be performed in order toensure obtainment of the dihydrochloride of Compound (I). In such cases,a base is generally used for desalination. Examples of the base are notlimited as long as they can perform desalination but include alkalimetal hydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide or cesium hydroxide, alkali earth metal hydroxides such asmagnesium hydroxide or calcium hydroxide, alkali earth metal oxides suchas magnesium oxide or calcium oxide, or amines such as ammonia,methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, ortributylamine. Preferably, the base is an alkali metal hydroxide or anamine. More preferably, the base is lithium hydroxide, sodium hydroxide,potassium hydroxide, tributylamine or ammonia.

The base can be added either directly or after being dissolved invarious solvents.

The amount of the base to be added is not limited but is generally inthe range of 1 to 4 equivalents per equivalent of various salts ofCompound (I).

In cases where hydrogen chloride or hydrochloric acid is added in orderto crystallize the hydrate of the dihydrochloride of Compound (I), theamount thereof is preferably greater than the amount required forCompound (I) to form the dihydrochloride thereof and precipitate out asthe crystalline form thereof. Moreover, the amount of hydrogen chlorideor hydrochloric acid to be added is generally in the range of 0.1 to 20equivalents and more preferably in the range of 2 to 10 equivalents perequivalent of Compound (I) in order to lower the solubility of thehydrate of the dihydrochloride of Compound (I) in solvents.

Examples of methods for concentrating the solution of Compound (I) orthe hydrate of the dihydrochloride thereof include a concentrationmethod which allows the solvent to evaporate by heating underatmospheric or reduced pressure by using a rotary evaporator or thelike, or a concentration method using a reverse osmosis membrane. Thereverse osmosis membrane to be used for condensing the solution may beselected from, for example, a polyacrylonitrile type membrane, apolyvinyl alcohol type membrane, a polyamide type membrane, a celluloseacetate type membrane and the like.

The temperature at which the hydrate of the dihydrochloride of Compound(I) is crystallized is generally in the range of −70 to 150° C., andpreferably −70 to 100° C.

Examples of good solvents to be used to manufacture the crystalline formin the present invention include, for example, water, alcohols such asmethanol or ethanol, ketones such as acetone or methylethylketone,ethers such as tetrahydrofuran or dioxane, nitriles such as acetonitrileor propionitrile, esters such as methyl acetate or ethyl acetate, amidessuch as dimethylformamide, dimethylacetamide or hexamethylphosphoricacid triamide, sulfoxides such as dimethylsulfoxide, or mixed solventsthereof. Preferably, methanol, tetrahydrofuran or mixed solvents thereofwith water are used.

Poor solvents to be used to manufacture the crystalline form in thepresent invention are selected in accordance with the solvents beingused as good solvents. Examples of the poor solvents include, forexample, water, C2 to C4 alcohols such as ethanol, propanol and butanol,ketones such as acetone or methylethylketone, ethers such as diethylether, esters such as ethyl acetate and propyl acetate, and nitrilessuch as acetonitrile, propionitrile and butyronitrile.

In cases where Crystalline form A is to be obtained, Crystalline form Acan be purified by forming an aqueous solution of Compound (I)(preferably, a mixed solution with tetrahydrofuran and water), andsubsequently hydrochloric acid is dripped thereto to enhance the purityof the crystalline form.

After dissolving or slurrying the obtained Crystalline form A in water,hydrochloric acid may be dripped thereto to further enhance the puritythereof.

In such cases, the purification effect can be enhanced by addition of abase before starting the drip of hydrochloric acid in some cases. Incases where a base is added, examples of the base are not limited to butgenerally include inorganic bases such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, magnesium hydroxide and calciumhydroxide; and organic bases such as trimethylamine, triethylamine,diisopropylethylamine and tributylamine. Preferably, sodium hydroxide orpotassium hydroxide is used.

The dissolution temperature or the slurry temperature in water is notlimited to but is generally in the range of 0 to 100° C. (refluxtemperature), preferably in the range of 20 to 100° C. (refluxtemperature), and more preferably in the range of 30 to 100° C. (refluxtemperature).

The duration of dissolution or slurrying is not limited to but isgenerally in the range of 5 minutes to 12 hours, and preferably in therange of 10 minutes to 6 hours.

In the case of slurrying, the drip of hydrochloric acid after slurryingmay be performed either after drying or without drying the crystallineform which is isolated after slurrying, or immediately after slurryingwithout isolation. Either way is acceptable.

The amount of hydrochloric acid to be used after dissolution orslurrying in water is not limited as long as it is greater than or equalto the amount required for Compound (I) to form the dihydrochloridethereof and precipitate out the crystalline form thereof. Hydrochloricacid is generally added until the resulting solution reaches a pHranging from 2 to 0.5 in order to lower the solubility of Crystallineform A to water.

Crystalline form A may be added as a seed crystalline form either beforestarting the drip of hydrochloric acid or during the drip thereof. Incases where a seed crystalline form is added, the amount of the seedcrystalline form to be added is not limited to but is generally in therange of 0.0001 to 20%, preferably 0.001 to 10%, and more preferably0.01 to 5% relative to the amount of Crystalline form A to be purified.

The temperature at which hydrochloric acid is dripped is generally inthe range of 0 to 100° C. (reflux temperature), preferably in the rangeof 20 to 100° C. (reflux temperature), and more preferably in the rangeof 50 to 100° C. (reflux temperature).

In cases where Crystalline form B in the present invention is to beobtained, the dihydrochloride of Compound (I) or the hydrate thereof iscrystallized from methanol (preferably anhydrous methanol).

As a starting material for the manufacture of Crystalline form A in thepresent invention, Compound (I), various salts of Compound (I), varioussolvates thereof, the dihydrochloride of Compound (I) or varioussolvates of the dihydrochloride of Compound (I), or the hydrate of thedihydrochloride of Compound (I) which itself is already isolated may beused. Alternatively, a solution of synthetic crude products containingCompound (I) may be used because the product can be purified bycrystallization. As a starting material for the manufacture ofCrystalline form B in the present invention, the dihydrochloride ofCompound (I) or the hydrate thereof is used.

Crystalline forms A or B which is precipitated out can be isolated by,for example, filtration, centrifugation or decantation and the like. Theisolated crystalline form may be rinsed with an adequate solvent asrequired. To rinse the crystalline form in the present invention,solvents, for example, water; alcohols such as methanol, ethanol andisopropanol; ketones such as acetone; esters such as methyl formate,ethyl formate, methyl acetate and ethyl acetate; aromatic hydrocarbonssuch as toluene and xylene; nitriles such as acetonitrile; ethers suchas diethylether and tetrahydrofuran, and mixed solvents thereof can beused. Preferably, water, methanol, tetrahydrofuran, or mixed solventsthereof are used.

The isolated crystalline form is dried generally in the range of 0 to150° C., and preferably in the range of 20 to 90° C. until the weightremains almost constant. Drying of the crystalline form may be performedin the presence of drying agents such as silica gel or calcium chloride,or under reduced pressure as required. Under reduced pressure, thecrystalline form can be dried without dehydrating the crystalline formwater by regulating temperature and pressure. In such cases, thepressure is regulated to be relatively high for a high dryingtemperature. For example, in cases where Crystalline form A in thepresent invention is dried, the pressure is set in the range of 0.7 to50 kPa, and preferably in the range of 1.8 to 11 kPa for the dryingtemperature at 50° C.

In cases where the dried crystalline form is dehydrated as a result ofdrying without regulating temperature and pressure, the driedcrystalline form may be subjected to moisture absorption generally underthe temperature range of 0 to 50° C. in 10 to 100% relative humidityrange, and preferably under the temperature range 10 to 40° C. in 20 to100% relative humidity range until the weight remains almost constant.The obtained crystalline form can be subjected to recrystallization andslurry purification to further improve the purity and quality of thecrystalline form.

Recrystallization of the crystalline form in the present invention isachieved by methods which are generally used in synthetic organicchemistry such as (1) dissolving by heating followed by cooling, (2) aconcentration method using solvent distillation after dissolving, and(3) precipitation of the crystalline form by dissolving in a goodsolvent followed by addition of a poor solvent thereto.

In cases where the crystalline form is dissolved in a solvent forrecrystallization, dehydrochlorination may occur. In such cases, thecrystalline form in the present invention can be obtained by addinghydrogen chloride or hydrochloric acid.

Slurry purification is a purification method wherein the crystallineform of a compound is suspended in an adequate solvent and is collectedagain by agitating the suspension.

Examples of solvents to be used for slurry purification of Crystallineform A in the present invention include esters such as methyl acetateand ethyl acetate; halogenated hydrocarbons such as methylene chlorideand chloroform; aromatic hydrocarbons such as toluene and xylene;ethanol; water; aliphatic hydrocarbons such as hexane; ethers such asdiisopropylether, diethylether and tetrahydrofuran; ketones such asacetone and methylethylketone; nitriles such as acetonitrile, and mixedsolvents thereof. Preferably, water, methanol, tetrahydrofuran, or mixedsolvents thereof are used. More preferably, water is used.

In cases where the crystalline form is suspended in a solvent for slurrypurification, dehydrochlorination may occur. In such cases, Crystallineform A can be obtained by adding hydrogen chloride or hydrochloric acid.

Examples of solvents to be used for slurry purification of Crystallineform B in the present invention include ketones such as acetone andmethylethylketone; esters such as methyl acetate and ethyl acetate;nitriles such as acetonitrile; halogenated hydrocarbons such asmethylene chloride and chloroform; aromatic hydrocarbons such as tolueneand xylene; alcohols such as ethanol and isopropanol; amides such asN,N-dimethylformamide; water; aliphatic hydrocarbons such as hexane;ethers such as tetrahydrofuran, diisopropylether and diethylether, andmixed solvents thereof. Preferably, water, methanol, tetrahydrofuran, ormixed solvents thereof are used. More preferably, water is used.

In cases where the crystalline form is suspended in a solvent for slurrypurification, dehydrochlorination may occur. In such cases, Crystallineform B can be obtained by adding hydrogen chloride or hydrochloric acid.

The crystalline form which is obtained by recrystallization and slurrypurification can be isolated and dried in a way similar to the methodsmentioned above.

It is known that Compound (I) and pharmacologically acceptable saltsthereof (particularly preferably, the hydrochloride salt thereof) have asignificant ability of peroxisome proliferator-activated receptor (PPAR)γ activation, as is disclosed in Japanese Patent No. 3488099 (WO99/18081, U.S. Pat. No. 6,432,993, European Patent No. 1022272) (PatentLiterature 1), Japanese Patent Laid-Open No. 2003-238406 (WO 03/053440)(Patent Literature 2), Japanese Patent Laid-Open No. 2004-083574 (WO2004/000356) (Patent Literature 3), Japanese Patent Laid-Open No.2005-162727 (WO 2004/083167) (Patent Literature 4), WO 2007/091622(Patent Literature 5) and the like.

In particular, WO 2007/091622 (Patent Literature 5) discloses thatCompound (I) and the hydrochloride salt thereof are useful as anticancerpharmaceutical compositions for preventing or treating stomach cancer,colon cancer, lung cancer, breast cancer, pancreas cancer, kidneycancer, prostate cancer, medulloblastoma, rhabdomyosarcoma, Ewing'ssarcoma, liposarcoma, multiple myeloma or leukemia.

More specifically, Test Example 1 in WO 2007/091622 (Patent Literature5) discloses along with experimental data that the dihydrochloride ofCompound (I) exerts a significant activity to suppress proliferation ofany cancer cells including human stomach cancer cells, human breastcancer cells, small cell lung cancer, pancreas cancer cells, prostatecancer cells, kidney cancer cells, medulloblastoma, human sarcoma cells(rhabdomyosarcoma, Ewing's sarcoma, liposarcoma) and multiple myeloma.

Also, Test Example 2 in the same pamphlet (Patent Literature 5)discloses along with experimental data that the dihydrochloride ofCompound (I) inhibits significantly proliferation suppressing activityin human leukemia cells.

In addition, Test Example 3 in WO 2007/091622 (Patent Literature 5)discloses that the dihydrochloride of Compound (I) exerts a significantantitumor activity in vivo against human colon cancer cell lines.

Moreover, Test Example 4 in the same pamphlet (Patent Literature 5)discloses that the administration of the dihydrochloride of Compound (I)in combination with an epidermal growth factor receptor (EGFR) inhibitorexerts a synergetic activity to suppress proliferation in cancer cells.

Also, Test Example 5 in the same pamphlet (Patent Literature 5)discloses that the dihydrochloride of Compound (I) exerts an antitumoractivity against human non-small cell lung cancer, and that theadministration of the same in combination with an epidermal growthfactor receptor (EGFR) inhibitor exerts an enhanced antitumor activity.

Moreover, Test Example 6 in the same pamphlet (Patent Document 5)discloses that the administration of the dihydrochloride of Compound (I)in combination with a vascular endothelial growth factor receptor(VEGFR) inhibitor or a Raf kinase inhibitor exerts a synergetic activityto suppress proliferation in cancer cells.

Furthermore, Test Example 7 in the same pamphlet (Patent Document 5)discloses that the dihydrochloride of Compound (I) exerts an antitumoractivity against human kidney cancer, and that the administration of thesame in combination with a vascular endothelial growth factor receptor(VEGFR) inhibitor or a Raf kinase inhibitor exerts an enhanced antitumoractivity.

Therefore, the crystalline form in the present invention is effective asa medicine, particularly as a PPAR γ activator, and is effective as anagent (anticancer pharmaceutical composition) for treating or preventingvarious cancers as described above.

In addition, Japanese Patent No. 3488099 (WO 99/18081, U.S. Pat. No.6,432,993, European Patent No. 1022272) (Patent Literature 1) disclosesthat Compound (I) and pharmacologically acceptable salts thereof have asignificant ability of peroxisome proliferator-activated receptor (PPAR)γ activation, a significant insulin resistance-improving action and ahypoglycemic action, and are also effective as agents for treating orpreventing diabetes (in particular, type 2 diabetes). Therefore, thecrystalline form in the present invention is effective as apharmaceutical composition for preventing or treating diabetes (inparticular, type 2 diabetes).

Moreover, the crystalline form in the present invention is effective asa pharmaceutical composition for preventing or treating cancers whenoccurring in conjunction with type 2 diabetes because it is ananticancer pharmaceutical composition as described above.

In cases where the crystalline form in the present invention is used asa medicine, particularly as a PPAR γ activator, an agent for treating orpreventing cancers, or an agent for treating or preventing diabetes, thecrystalline form can be administered either by itself or mixed with anappropriate and pharmacologically acceptable diluting agent or dilutionagent and the like to form, for example, tablets, capsules, granules,powders or syrups for oral administration, or to form, for example,injectable solutions or suppositories for parenteral administration.

The preparations are manufactured by known methods using additives suchas diluting agents (for example, sugars such as lactose, sucrose,glucose and sorbitol; derivatives of starch such as corn starch, potatostarch, α-starch, dextrin and carboxymethylstarch; derivatives ofcellulose such as crystalline cellulose, hydroxypropylmethyl cellulose,carboxymethyl cellulose, calcium carboxymethylcellulose and internallycross-linked sodium carboxymethylcellulose; gum arabic; dextran;pullulan; silicates such as synthetic aluminum silicate and magnesiumaluminometasilicate; phosphates such as calcium phosphate; carbonatessuch as calcium carbonate; and hydrosulfates such as calcium sulfate),binders (for example, the above mentioned diluting agents; gelatin;polyvinylpyrrolidone; and macrogol), disintegrating agents (for example,the above mentioned diluting agents; chemically modified derivatives ofstarch or cellulose such as sodium croscarmellose, sodium carboxymethylstarch, cross-linked polyvinylpyrrolidone), lubricating agents (forexample, talc; stearic acid; metallic stearates such as calcium stearateand magnesium stearate; colloid silica; veegum; waxes such as beeswaxand whale wax; acidum boricum; glycol; carboxylic acids such as fumaricacid and adipic acid; sodium salts of carboxylic acids such as sodiumbenzoate; hydrosulfates such as sodium sulfate; leucine; lauryl sulfatessuch as sodium lauryl sulfate and magnesium lauryl sulfate; silicatessuch as light anhydrous silicic acid and silicic acid hydrates;derivatives of starch as described in the above mentioned dilutingagents), fixing agents (for example, para-hydroxy benzoate esters suchas methylparaben and propylparaben; alcohols such as chlorobutanol,benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenolssuch as phenol and cresol; thimerosal; acetic acid anhydride; andsorbate), corrigents (for example, edulcorants, acidulants and fragrantmaterials which are generally used), suspending agents (for example,polysorbate 80 and sodium carboxymethyl cellulose), dilution agents, andsolvents for preparation (for example, water, ethanol and glycerin).

The amount of the crystalline form of the present invention used mayvary in accordance with the degree of symptoms, body weight and age ofthe patients (mammals, in particular humans) being administered, mode ofadministration and the like. For example, the recommended dose is in therange of a minimum of 0.001 mg/kg body weight (preferably 0.01 mg/kgbody weight) to a maximum of 500 mg/kg body weight (preferably 50 mg/kgbody weight) per dose for oral administration, and in the range of aminimum of 0.005 mg/kg body weight (preferably 0.05 mg/kg body weight)to a maximum of 50 mg/kg body weight (preferably 5 mg/kg body weight)per dose for intravenous administration. It is preferred to administerthe agents once to several times per day in accordance to the degree ofsymptoms.

EXAMPLES

The present invention will now be described in connection with certainexamples, test examples and preparation examples more specificallyhereinafter.

Example 1 Crystalline Form A

(1-1)

4.0 g of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionehydrochloride obtained by a method similar to the method described inExample 8 of Japanese Patent No. 3488099 was suspended in a mixture oftetrahydrofuran (40 ml) and water (12 ml) at room temperature under anitrogen atmosphere, and 2.4 g of 25% sodium hydroxide aqueous solutionwas dripped thereto to form a solution. The resulting solution wasdripped to a suspension of activated carbon prepared under a nitrogenatmosphere (0.4 g) in tetrahydrofuran (12 ml) and the mixture wasagitated for 20 minutes at the same temperature. After filtering off theactivated carbon, the activated carbon was rinsed with 12 ml oftetrahydrofuran. The filtrate and the washing solution were combined,and 12 ml of water was added thereto. A mixed solution of 38%hydrochloric acid (3.2 g) and tetrahydrofuran (12 ml) was dripped to theresulting solution. The reaction mixture was agitated for 45 minutes.The mixture was cooled to 0° C. and further agitated for 2 hours. Theobtained crystalline form was filtered off and was dried for 12 hours ata pressure of approximately 80 Pa and at 50° C. The crystalline form wasleft in the atmosphere for 3 hours to give 3.64 g of a crystalline formof a monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride.

(1-2)

2.0 g of the crystalline form obtained in (1-1) was suspended in 40 mlof water and the suspension was agitated for 20 minutes at 80° C. Amixture of 38% hydrochloric acid (1.1 g) and water (8.4 ml) was drippedthereto for 5 minutes at the same temperature. The reaction mixture wasthen agitated for 1 hour and was cooled to 40° C. The crystalline formwas filtered off and rinsed with 6 ml of water to give a hygroscopiccrystalline form of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride. The obtained crystalline form was dried for 14 hours ata pressure of approximately 80 Pa and at 50° C. The crystalline form waslet to sit in the atmosphere for 3 hours to give 1.83 g of the whitecrystalline form of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride, wherein the crystalline form had the crystal formshowing the diffraction pattern obtained by X-ray powder diffractiondescribed in FIG. 1 (Crystalline fowl A).

(1-3)

FIG. 1 shows the diffraction pattern obtained by X-ray powderdiffraction (Cu Kα, λ=1.54 angstroms) for the crystalline form obtainedin (1-2). Table 1 shows the peaks which have relative intensitiesgreater than or equal to 10 based on the intensity 100 of the largestpeak based on the diffraction pattern described in FIG. 1. Numbers inFIG. 1 correspond to peak numbers in Table 1.

TABLE 1 Peak d Relative number 2θ value intensity 1 8.18 10.80 25 2 8.5810.30 11 3 12.52 7.06 100 4 14.90 5.94 13 5 14.98 5.91 14 6 15.28 5.7946 7 16.02 5.53 28 8 16.32 5.43 43 9 17.56 5.05 14 10 18.88 4.70 24 1119.38 4.58 11 12 20.00 4.44 38 13 20.48 4.33 25 14 21.24 4.18 30 1521.94 4.05 17 16 22.36 3.97 34 17 22.72 3.91 42 18 23.16 3.84 24 1923.48 3.79 17 20 24.14 3.68 40 21 24.62 3.61 18 22 25.12 3.54 16 2325.54 3.48 76 24 27.50 3.24 19 25 28.72 3.10 14 26 28.98 3.08 14 2729.74 3.00 17 28 30.06 2.97 31 29 30.68 2.91 17 30 31.76 2.82 10 3132.80 2.73 12 32 33.20 2.70 14 33 35.50 2.53 11

Among these peaks, the peaks at interplanar spacings (d values) of 7.06,5.79, 5.43, 4.44, 4.18, 3.97, 3.91, 3.68, 3.61, 3.48, 3.24 and 2.97angstroms are particularly distinctive of Crystalline form A.

(1-4)

FIG. 2 shows a differential thermal analysis (DSC) chart.

Example 2 Crystalline Form A

(2-1)

2.0 g of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionehydrochloride obtained by a method similar to the method described inExample 8 of Japanese Patent No. 3488099 was suspended in a mixture oftetrahydrofuran (20 ml) and water (6 ml) at room temperature under anitrogen atmosphere, and 1.2 g of 25% sodium hydroxide aqueous solutionwas dripped thereto to form a solution. The resulting solution wasdripped to a suspension of activated carbon prepared under a nitrogenatmosphere (0.2 g) in tetrahydrofuran (6 ml) and the mixture wasagitated for 20 minutes at the same temperature. After filtering off theactivated carbon, the activated carbon Was rinsed with 6 ml oftetrahydrofuran. The filtrate and the washing solution were combined,and 6 ml of water was added thereto. A mixed solution of 38%hydrochloric acid (1.6 g) and tetrahydrofuran (6 ml) was dripped to theresulting solution. The reaction mixture was agitated for 45 minutes.The mixture was cooled to 0° C. and further agitated for 2 hours. Theobtained crystalline form was filtered off and rinsed with water to givea moist crystalline form of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride.

(2-2)

The moist crystalline form obtained in (2-1) was suspended in 40 ml ofwater and the suspension was agitated for 20 minutes at 80° C. A mixtureof 38% hydrochloric acid (1.1 g) and water (8.4 ml) was dripped theretofor 5 minutes at the same temperature. The reaction mixture was thenagitated for 1 hour and was cooled to 40° C. The crystalline form wasfiltered off and rinsed with 6 ml of water to give a moist crystallineform of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride. The obtained moist crystalline form was dried for 12hours at a pressure of 4.3 kPa and at 50° C. to give a white crystallineform of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride, wherein the crystalline form has the crystal formdescribed in claim 2. The X-ray powder diffraction pattern and thedifferential thermal analysis chart of this crystalline form matchedthose for Crystalline form A obtained in Example 1.

Example 3 Crystalline Form A

(3-1)

2.0 g of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride obtained by a method similar to the method described inExample 1-1 was suspended in 100 ml of water. The resulting suspensionwas refluxed for 2 hours. The reaction mixture was cooled to 0° C. andagitated for 1 hour. The obtained crystalline form was filtered off andrinsed with water. The obtained moist crystalline form was dried for 14hours at a pressure of approximately 80 kPa and at 50° C. to give acrystalline form, wherein the proportion of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneand hydrochloric acid was approximately 1 to 1.1.

(3-2)

The crystalline form obtained in (3-1) was suspended in 40 ml of water.A mixture of 38% hydrochloric acid (1.1 g) and water (8.4 ml) wasdripped thereto for 5 minutes at 80° C. The reaction mixture was thenagitated for 1 hour and was cooled to 0° C. The crystalline form wasfiltered off and rinsed with 6 ml of water to give a moist crystallineform of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride. The obtained crystalline form was dried for 14 hours ata pressure of approximately 80 Pa and at 50° C. The crystalline form wasleft in the atmosphere for 3 days to give 1.83 g of a white crystallineform of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride, wherein the crystalline form has the crystal formdescribed in claim 2. The X-ray powder diffraction pattern and thedifferential thermal analysis chart of this crystalline form matchedthose for Crystalline form A obtained in Example 1.

Example 4 Crystalline Form A

4.0 g of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride obtained by a method similar to the method described inExample (1-1) were suspended in 160 ml of water under a nitrogenatmosphere, and 1.08 g of a 25% sodium hydroxide aqueous solution weredripped thereto at 80° C. The resulting mixture was agitated for 1 hour.The mixture was then cooled to 65° C., and a mixed solution of 38%hydrochloric acid (0.65 g) and water (4 ml) was dripped thereto at thesame temperature. After adding 0.2 g of Crystalline form A thereto, theresulting solution was agitated for 1 hour, and a mixed solution of 38%hydrochloric acid (5.11 g) and water (31.6 ml) was dripped thereto for 1hour at the same temperature. The reaction mixture was then agitated for30 minutes at the same temperature, and was cooled to 40° C. Theobtained crystalline form was filtered off and rinsed with a mixedsolution of 38% hydrochloric acid (0.31 g) and water (12 ml). Theobtained crystalline form was dried for 17 hours at a pressure ofapproximately 4.3 kPa and at 50° C. to give 3.98 g of Crystalline formA. The X-ray powder diffraction pattern and differential thermalanalysis chart of this crystalline form matched those for Crystallineform A obtained in Example 1.

Example 5 Crystalline Form A

5.0 g of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride obtained by a method similar to the method described inExample (1-1) were suspended in 300 ml of water under a nitrogenatmosphere, and 1.94 g of 38% hydrochloric acid were dripped thereto.The resulting mixture was agitated at 95° C. to form a solution. A mixedsolution of 38% hydrochloric acid (0.81 g) and water (5 ml) was drippedthereto at the same temperature. After adding 0.25 g of Crystalline formA thereto, the resulting mixture was agitated for 30 minutes, and amixed solution of 38% hydrochloric acid (6.14 g) and water (38 ml) wasdripped thereto for 2 hour at the same temperature. The reaction mixturewas then agitated for 30 minutes, and was cooled to 40° C. The obtainedcrystalline form was filtered off and rinsed with a mixed solution of38% hydrochloric acid (0.39 g) and water (15 ml). The obtainedcrystalline form was dried for 16 hours at a pressure of approximately4.3 kPa and at 50° C. to give 5.01 g of Crystalline form A. The X-raypowder diffraction pattern and differential thermal analysis chart ofthis crystalline form matched those for Crystalline form A obtained inExample 1.

Example 6 Crystalline Form B

(6-1)

2.5 g of the crystalline form of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride obtained by the same method as the method described inExample 1 was suspended in 50 ml of methanol and was dissolved at 60° C.The resulting solution was cooled to 0° C. and agitated for 26 hours atthe same temperature. The obtained crystalline form was dried for 16hours at a pressure of approximately 80 Pa and at 50° C. to give anapproximately hemihydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride.

(6-2)

The crystalline form of the approximately hemihydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride obtained in (6-1) was let to sit for 19 hours at roomtemperature under approximately 100% relative humidity to give 1.6 g ofthe white crystalline form of the monohydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride, wherein the crystalline form had the crystal formshowing the diffraction pattern obtained by X-ray powder diffractiondescribed in FIG. 3 (Crystalline form B).

(6-3)

FIG. 3 shows the diffraction pattern obtained by X-ray powderdiffraction (Cu Kα, λ=1.54 angstroms) for the crystalline form obtainedin (6-2). Table 2 shows the peaks which have relative intensitiesgreater than or equal to 7 based on the intensity 100 of the largestpeak based on the diffraction pattern described in FIG. 3. Numbers inFIG. 3 correspond to peak numbers in Table 2.

TABLE 2 Peak d Relative number 2θ value intensity 1 8.12 10.88 8 2 8.4810.42 25 3 12.80 6.91 12 4 13.12 6.74 7 5 15.12 5.85 44 6 15.66 5.65 9 716.04 5.52 24 8 16.28 5.44 11 9 16.96 5.22 9 10 17.68 5.01 14 11 19.224.61 12 12 20.38 4.35 11 13 20.68 4.29 19 14 21.72 4.09 18 15 21.98 4.047 16 22.44 3.96 8 17 23.16 3.84 45 18 23.60 3.77 7 19 24.70 3.60 7 2024.98 3.56 13 21 25.72 3.46 100 22 26.08 3.41 10 23 27.84 3.20 8 2428.06 3.18 8 25 29.16 3.06 8 26 30.30 2.95 22 27 31.64 2.83 19 28 34.382.61 7 29 34.96 2.56 9

Among these peaks, the peaks at interplanar spacings (d values) of10.42, 5.85, 5.52, 3.84, 3.46 and 2.95 angstroms are particularlydistinctive of Crystalline form B.

(6-4)

FIG. 4 shows a differential thermal analysis (DSC) chart.

Comparative Example 1

5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionehydrochloride was manufactured by the method described in Example 8 ofJapanese Patent No. 3488099. The obtained compound exhibited a faint redpurple color. FIG. 5 shows the diffraction pattern obtained by X-raypowder diffraction (Cu Kα, λ=1.54 angstroms) for this compound.

TEST EXAMPLES Test Example 1 Content Measurement

The contents of Crystalline form A obtained in Example 1 and thecompound obtained in Comparative Example 1 (the hydrochloride salt of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneobtained by a method similar to the method described in Example 8 ofJapanese Patent No. 3488099, which was used as a material as describedin Example 1, this is also the case in Test Examples 2-4) were measuredby the analysis method below by using HPLC.

0.01 mol/ml ammonium acetate buffer was prepared by adding a 0.01 mol/mlammonium acetate aqueous solution to a 0.01 mol/ml acetic acid aqueoussolution and adjusting to pH=4.5.

Water, acetonitrile and methanol were mixed at a proportion of 55:40:5by volume to give a sample dissolution solution.

0.2 g of isoamyl 4-hydroxybenzoate were dissolved in the sampledissolution solution to bring the total volume to 200 ml to give aninternal standard solution.

Approximately 0.03949 g of the standard of the5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride monohydrate were precisely measured, transferred to a200 ml volumetric flask, and dissolved in the sample dissolutionsolution to bring the total volume to 200 ml. 5 ml of the resultingsolution were precisely measured, transferred to a 50 ml volumetricflask, and 10 ml of the internal standard solution were precisely addedthereto. The sample dissolution solution was further added thereto tobring the total volume to 50 ml to give a standard solution.

Approximately 0.01 g of the subject for content measurement wasprecisely measured, transferred to a 10 ml volumetric flask, andapproximately 2.5 ml of dimethylsulfoxide were added thereto to bring itinto solution. The sample dissolution solution was further added theretoto bring the total volume to 10 ml. 2 ml of the resulting solution wereprecisely measured, transferred to a 100 ml volumetric flask, and 20 mlof the internal standard solution were precisely added thereto. Thesample dissolution solution was further added thereto to bring the totalvolume to 100 ml to give a sample solution.

Contents were measured under the conditions below.

Detector: UV absorptiometer (wavelength: 290 nm)

Column: Waters Corporation, Symmetry C18 (4.6 mm×100 mm)

Column temperature: 40° C.

Mobile phase: 0.01 mol/ml ammonium acetate buffer-acetonitrile (3:2)

Flow rate: 1 ml/min (Under the present conditions,5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dioneshowed a retention time of approximately 8 minutes.)

Injection amount of the standard solution and the sample solution: 10 μl

Peak area measurement range: Approximately 20 minutes after the start ofthe injection.

Contents are given by the following formula.Content(%)=(Q _(T) ×W _(S) ×F _(P))÷(Q _(S) ×W _(T))whereinweighing amount of the standard at the time of preparation of thestandard solution (g): W_(S);weighing amount of the sample at the time of preparation of the samplesolution (g): W_(T);purification coefficient of the standard: F_(P);the value of the peak area for the standard divided by the peak area forthe internal standard in the chromatogram of the standard solution:Q_(S); andthe value of the peak area for the sample divided by the peak area forthe internal standard in the chromatogram of the sample solution: Q_(T).

The obtained measurement results are shown in Table 3.

TABLE 3 Compound obtained in Crystalline form A Comparative Example 1obtained in Example 1 Content (%) 87.0 96.5

It is shown that Crystalline form A in the present invention has asignificantly enhanced purity compared to5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionehydrochloride (the compound of Comparative Example 1), which had beenconventionally obtained, and, at the same time, the method for obtainingCrystalline form A in the present invention has a high purificationeffect.

Test Example 2 Impurity

The impurity content ratio in Crystalline form A obtained in Example 1and the compound obtained in Comparative Example 1 was measured by theanalysis method below by using HPLC.

The term impurity content ratio here represents the ratio of theintegration area for all peaks whose peak area ratios are measured asequal or above 0.01%, excluding the peak for Compound (I) and the peakwhich is detected when injecting a solvent alone, to the peak area forCompound (I) under the below described measurement conditions.

Moreover, the term individual impurity represents a peak area ratio fora peak whose peak area ratio is measured as equal or above 0.01%,excluding the peak for Compound (1) and the peak which is detected wheninjecting a solvent alone.

0.01 mol/ml ammonium acetate buffer was prepared by adding a 0.01 mol/mlammonium acetate aqueous solution to a 0.01 mol/ml acetic acid aqueoussolution and adjusting to pH=4.5.

Water and acetonitrile were mixed at a proportion of 3:2 by volume togive a sample dissolution solution.

0.01 g of the subject for measurement was precisely measured,transferred to a 20 ml brown volumetric flask, and approximately 1 ml ofdimethylsulfoxide was added thereto to form a solution. The total volumewas then brought to 20 ml to give a sample solution.

1 ml of the sample solution was precisely measured, transferred to a 100ml brown volumetric flask. The sample dissolution solution was addedthereto to bring the total volume to 100 ml to give a standard solution.

Measurements were conducted under the conditions below.

HPLC Measurement Conditions (1)

Detector: UV absorptiometer (wavelength: 230 nm)

Column: Waters Corporation, XTerra RP₁₈ (4.6 mm×150 mm)

Column temperature: 40° C.

Mobile phase: 0.01 mol/ml ammonium acetate buffer-acetonitrile (65:35)

Flow rate: 1 ml/min (Under the present conditions, Compound (1) showed aretention time of approximately 25 minutes.)

Injection amount of the standard solution and the sample solution: 10 μl

Area measurement range: 70 minutes after the start of the injection.

HPLC Measurement Conditions (2)

Detector: UV absorptiometer (wavelength: 230 nm)

Column: Waters Corporation, XTerra RP₁₈ (4.6 mm×150 mm)

Column temperature: 40° C.

Mobile phase: 0.01 mol/ml ammonium acetate buffer-acetonitrile (56:44)

Flow rate: 1 ml/min (Under the present conditions, Compound (1) showed aretention time of approximately 8 minutes.)

Injection amount of the standard solution and the sample solution: 10 μl

Area measurement range: 70 minutes after the peak which elutes next tothe peak whose retention time relative to Compound (I) is 1.48.

Impurity content ratios were calculated by the following formula.Impurity content ratio(%)=[The sum of the individual impurities above0.01% measured under HPLC Measurement Conditions(1)]+[The sum of theindividual impurities above 0.01% measured under HPLC MeasurementConditions(2)]whereinthe sum of the individual impurities above 0.01% measured under HPLCMeasurement Conditions (1) (%)=A_(i1)/A_(S1); andthe sum of the individual impurities above 0.01% measured under HPLCMeasurement Conditions (2) (%)=A_(i2)/A_(S2)

wherein the above formula

the peak area for Compound (I) in the standard solution measured underHPLC Measurement Conditions (1): A_(S1);

the peak area for individual impurities above 0.01% measured under HPLCMeasurement Conditions (1): A_(i1);

the peak area for compound (1) in the standard solution measured underHPLC Measurement Conditions (2): A_(S2); and

the peak area for individual impurities above 0.01% measured under HPLCMeasurement Conditions (2): A_(i2).

The obtained measurement results are shown in Table 4.

TABLE 4 Impurity in Impurity in Relative compound obtained CrystallineMeasurement retention time in Comparative form A method [h] Example 1(%) in Example 1 (%) HPLC 0.13 0.10 — Measurement 0.189 0.14 —conditions (1) 0.192 0.24 0.02 0.35 0.51 0.24 0.88 1.06 <0.01 1.15 1.570.68 1.19 0.10 — 1.71 0.10 0.05 Others 0.75 0.11 HPLC 2.06 0.18 0.05measurement 3.98 0.20 0.09 conditions (2) Others 0.30 0.14 Impuritycontent ratio [%] 5.25 1.38

It is shown that the method for obtaining Crystalline form A in thepresent invention has a high impurity removal effect.

Test Example 3 Residual Solvent

Residual solvents in Crystalline form A and Crystalline form B obtainedin Examples, and in the compound obtained in Comparative Example 1 weremeasured by gas chromatography in accordance with the analysis methodbelow.

(1) Method for Preparing Samples of Crystalline Form A and CrystallineForm B

Dimethylformamide and water were mixed at a proportion of 7:3 by volumeto give a dilute solution.

1 ml of t-butyl alcohol was precisely measured, transferred to a 100 mlvolumetric flask, and dissolved to the dilute solution to bring thetotal volume to 100 ml. 10 ml of the resulting solution were preciselymeasured, transferred to a 500 ml volumetric flask, and the dilutesolution was added thereto to bring the total volume to 500 ml to givean internal standard solution.

2 ml of tetrahydrofuran, 2 ml of diisopropyl ether, 2 ml of methanol, 2ml of acetic ethyl, 2 ml of acetic acid, and 2 ml of 1,4-dioxane wereprecisely measured, transferred to a 250 ml volumetric flask, and theinternal standard solution was added thereto to bring the total volumeto 250 ml. 1 ml of the resulting solution was precisely measured,transferred to a 100 ml volumetric flask, and the internal standardsolution was added thereto to bring the total volume to 100 ml. 6 ml outof 100 ml of the resulting solution were precisely measured, andtransferred to a 20 ml headspace vial container. The vial container wasclosed using a rubber plug, and stoppered tightly by twisting andclosing an aluminum cap to give a standard solution.

0.1 g of the sample for measurement was precisely measured, transferredto a 20 ml headspace vial container, and 6 ml of the internal standardsolution were precisely added thereto. The vial container was closedusing a rubber plug, and stoppered tightly by twisting and closing analuminum cap. The sample was completely dissolved while shaking in awater bath at a temperature ranging from 60 to 70° C. to give a samplesolution.

(2) Method for Preparing Sample of the Compound in Comparative Example 1

1 ml of t-butyl alcohol was precisely measured, transferred to a 100 mlvolumetric flask, and dissolved to chlorobenzene to bring the totalvolume to 100 ml. 10 ml of the resulting solution were preciselymeasured, transferred to a 500 ml volumetric flask, and chlorobenzenewas added thereto to bring the total volume to 500 ml to give aninternal standard solution.

2 ml of tetrahydrofuran, 2 ml of diisopropyl ether, 2 ml of methanol, 2ml of acetic ethyl, 2 ml of acetic acid, and 2 ml of 1,4-dioxane wereprecisely measured, transferred to a 250 ml volumetric flask, and theinternal standard solution was added thereto to bring the total volumeto 250 ml. 1 ml of the resulting solution was precisely measured,transferred to a 100 ml volumetric flask, and the internal standardsolution was added thereto to bring the total volume to 100 ml. 6 ml outof 100 ml of the resulting solution were precisely measured, andtransferred to a 20 ml headspace vial container. The vial container wasclosed using a rubber plug, and stoppered tightly by twisting andclosing an aluminum cap to give a standard solution.

0.1 g of the sample for measurement was precisely measured, transferredto a 20 ml headspace vial container, and 6 ml of the internal standardsolution and 100 μl of tributylamine were precisely added thereto. Thevial container was closed using a rubber plug, and stoppered tightly bytwisting and closing an aluminum cap. The sample was completelydissolved while shaking in a water bath at the temperature ranging from60 to 70° C. to give a sample solution.

(3) Test Condition

Residual levels of solvents were measured under the test conditionsbelow.

Detector: Hydrogen flame ionization detector

Column: J&W Inc., DB-624 (0.53 mm×30 m)

Column temperature: 40° C. (hold 5 minutes)→Temperature rise at a rateof 10° C./min→260° C. (hold 3 minutes)

Temperature of sample vaporizing chamber: 250° C.

Detector temperature: 300° C.

Carrier gas: Helium

Column flow rate: 5 ml/min (Column flow rate was adjusted to obtain aretention time of approximately 7 minutes for tetrahydrofuran.)

Split ratio: 1:10

Sample injection method: Split method

Area measurement range: 20 minutes

(4) Operating Condition for the Headspace Apparatus

Equilibrium temperature inside the vial (oven temperature): 85° C.

Equilibrium time inside the vial: 15 minutes

Injection line temperature

Sample loop temperature: 95° C.

Transfer line temperature: 110° C.

Carrier gas: Helium

Vial pressure time: 0.20 minutes

Vial pressure: Approximately 10 kPa

Sample loop fill time: 0.15 minutes

Sample loop equilibrium time: 0.05 minutes

Injection time: 1.0 minute

Sample injection amount: 1 ml

(5) Method for Calculating Residual Solvent

Residual level of each solvent is given by the following formula.Residual level of each solvent(ppm)=(2×D×Q _(T)×6×10000000)÷(Q_(S)×25000×W)

wherein

weighing amount of the sample (g): W;

density of each solvent (g/ml): D;

the ratio of the area for each solvent in the standard solution to thepeak area for the internal standard substance: Q_(S); and

the ratio of the area for each solvent in the sample solution to thepeak area for the internal standard substance: Q_(T)

The obtained measurement results are shown in Table 5.

TABLE 5 Residual level in compound Residual level in Residual level inobtained in Crystalline form Crystalline form Comparative A obtained inB obtained in Example 1 Example 1 Example 6 Solvent name (ppm) (ppm)(ppm) Methanol  25 ND 1385 Ethanol 1713 ND ND Hexane ND ND NDDiisopropyl ethyl ND ND ND Acetic ether 9297 ND ND Tetrahydrofuran ND271 ND Acetic acid 3892 ND ND 1,4-dioxane ND ND ND Total 14926  271 1385

It is shown that there is only one kind of residual solvent inCrystalline form A and Crystalline form B in the present invention, andthe amounts are extremely low.

Test Example 4 Color Tone

Approximately 1 g of the test substance was placed on a sheet of whitepaper to observe its color tone. The test results are shown in Table 6.

TABLE 6 Compound obtained in Crystalline form A Comparative Example 1obtained in Example 1 Color tone Faint red purple White

It is shown that the method for obtaining Crystalline form A in thepresent invention has a high decolorization effect.

Test Example 5 Solubility Test

Solubilities of Crystalline form A and Crystalline form B of Compound(I) in a simulated gastric fluid were measured by the method below (freebody conversion).

10 times concentrated Liquid 1 used for the disintegration test of theJapanese Pharmacopoeia (purchased from Kanto Chemical Co., Inc.) wasdiluted 10-fold with purified water to give a simulated gastric fluid.Approximately 80 mg of the crystalline form for measurement wereprecisely measured, transferred to a 25 ml volumetric flask, anddissolved in methanol to bring the total volume to 25 ml. 2 ml of theresulting solution were transferred to a 50 ml volumetric flask, and thesimulated gastric fluid was added thereto to bring the total volume to50 ml to give a standard solution.

By using an elution testing machine NTR-6100A (Toyama Sangyo Co., Ltd.),approximately 100 mg of the subject crystalline form were added to 500ml of the simulated gastric fluid at 37° C., and agitated with a paddle(250 rpm). After 60 minutes, samples were taken from the test solution.The absorbance of the standard solution and test solution samples wasmeasured at 289 nm and 360 nm by using a UV visible spectrophotometer.

Solubility is calculated by the following formula.Solubility(μg/ml)={(A _(S289) −A _(S360))×W _(S)×1000×502.58}÷{(A_(T289) −A _(T360))×625×593.52}

wherein

weighing amount of the crystalline form used for the preparation of thestandard solution (mg): W_(S);

absorbance of the standard solution at 289 nm: A_(S289);

absorbance of the standard solution at 360 nm: A_(S360);

absorbance of the test solution at 289 nm: A_(T289);

absorbance of the test solution at 360 nm: A_(T360);

molecular weight of the dihydrochloride monohydrate of Compound (I):593.52; and

molecular weight of the free body of Compound (I): 502.58

The obtained test results are shown in Table 7.

TABLE 7 Crystalline form A Crystalline form B Solubility (μg/ml) 76.92155.25

Crystalline form A and Crystalline form B in the present inventionshowed sufficient solubility as a pharmaceutical ingredient.

PREPARATION EXAMPLES Preparation Example 1 Capsule

After 5 g of Crystalline form A obtained in Example 1 are mixed with 115g of lactose, 58 g of corn starch and 2 g of magnesium stearate in aV-type mixing machine, 180 mg of the mixture is filled in a capsule No.3 to give the capsules thereof.

Preparation Example 2 Tablet

After 5 g of Crystalline form A obtained in Example 1 is mixed with 90 gof lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 gof magnesium stearate in a V-type mixing machine, the mixture iscompressed in a tabletting machine to give tablets weighing 150 mg each.

Preparation Example 3 Suspension

A dispersion medium is prepared, wherein methylcellulose is diffused anddissolved in purified water. Crystalline form A obtained in Example 1 isplaced in a mortar after weighing and kneaded well while adding theretothe above mentioned dispersion medium in small portions. Purified wateris added to prepare 100 g of the suspension.

The invention claimed is:
 1. A crystalline form of a hydrate of adihydrochloride of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionerepresented by the following formula:

wherein the crystalline form shows main peaks at interplanar spacings of10.42, 5.85, 5.52, 3.84, 3.46 and 2.95 angstroms in X-ray powderdiffraction obtained with Cu Kα line radiation (wavelength λ=1.54angstroms).
 2. A method of manufacturing the crystalline form accordingto claim 1, comprising recrystallizing a hydrate of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionedihydrochloride from methanol and subjecting the hydrate to moistureabsorption at a temperature of 0 to 50° C. in a 20 to 50% relativehumidity range until the weight remains always constant.
 3. A method oftreating diabetes in a mammal comprising administering to a mammal inneed thereof a pharmaceutically effective amount of the crystalline formaccording to claim
 1. 4. The method according to claim 3, wherein themammal is a human.
 5. The method according to claim 4, wherein thediabetes is type 2 diabetes.
 6. The method according to claim 3, whereinthe method is for treating a human.
 7. A method of treating a cancer ina mammal, wherein the cancer is stomach cancer, colon cancer, lungcancer, breast cancer, pancreatic cancer, kidney cancer, prostatecancer, medulloblastoma, rhabdomyosarcoma, Ewing's sarcoma, liposarcoma,multiple myeloma or leukemia, comprising administering to a mammal inneed thereof a pharmaceutically effective amount of the crystalline formaccording to claim
 1. 8. The method according to claim 7, wherein themammal is a human.
 9. The method according to claim 7, wherein themethod is for treating a human.
 10. A method of treating diabetes in amammal comprising administering to a mammal in need thereof apharmaceutically effective amount of a crystalline form of a hydrate ofa dihydrochloride of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionerepresented by the following formula:

wherein the crystalline form shows main peaks at interplanar spacings of7.06, 5.79, 5.43, 4.44, 4.18, 3.97, 3.91, 3.68, 3.61, 3.48, 3.24 and2.97 angstroms in X-ray powder diffraction obtained with Cu Kα lineradiation (wavelength λ=1.54 angstroms).
 11. The method according toclaim 10, wherein the mammal is a human.
 12. The method according toclaim 11, wherein the diabetes is type 2 diabetes.
 13. The methodaccording to claim 10, wherein the method is for treating a human.
 14. Amethod of treating cancer in a mammal, wherein the cancer is stomachcancer, colon cancer, lung cancer, breast cancer, pancreatic cancer,kidney cancer, prostate cancer, medulloblastoma, rhabdomyosarcoma,Ewing's sarcoma, liposarcoma, multiple myeloma or leukemia, comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a crystalline form of a hydrate of a dihydrochloride of5-(4-{[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1-H-benzimidazol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dionerepresented by the following formula:

wherein the crystalline form shows main peaks at interplanar spacings of7.06, 5.79, 5.43, 4.44, 4.18, 3.97, 3.91, 3.68, 3.61, 3.48, 3.24 and2.97 angstroms in X-ray powder diffraction obtained with Cu Kα lineradiation (wavelength λ=1.54 angstroms).
 15. The method according toclaim 14, wherein the mammal is a human.
 16. The method according toclaim 14, wherein the method is for treating a human.
 17. The methodaccording to claim 15, wherein the cancer is colon cancer.
 18. Themethod according to claim 15, wherein the cancer is breast cancer. 19.The method according to claim 15, wherein the cancer is pancreaticcancer.
 20. The method according to claim 15, wherein the cancer iskidney cancer.
 21. The method according to claim 15, wherein the canceris prostate cancer.
 22. The method according to claim 15, wherein thecancer is liposarcoma.
 23. A method of preparing a PPAR_(γ) activatorcomprising mixing an effective amount of the crystalline form accordingto claim 1 and a pharmacologically acceptable additive.